Cyclic triazo and diazo sodium channel blockers

Abstract

A method of treating a disorder such as epilepsy, multiple sclerosis, glaucoma and uveitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia, or trigeminal autonomic cephalalgias. The method includes administering to a subject in need thereof substituted 1,2,4-triazine compounds of formula (I): Each of A, N*, X, Y, Z, R1, and R2 is defined herein. Also disclosed are compounds of the formula and a pharmaceutical composition containing such a compound.

What is claimed is: 
     
       1. A method of treating a disorder comprising administering to a subject in need thereof a compound of general formula (I), or a salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       in which:
 X and Y are each N; 
 Z is a single bond or an optionally substituted linking group; 
 R1 is hydrogen, or a substituent group, or the Y nitrogen is unsubstituted; 
 R2 is amino or a substituent group; 
 N* is amino when R1 is hydrogen or ═NH when R1 is a substituent group; or 
 N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or 
 N* is an optionally substituted piperazinyl ring; and 
 A is a sulphur containing heterocycle substituted with halogen, alkyl or alkoxy; 
 wherein the disorder is a neurodegenerative disorder, motor neurone disease, Alzheimer's disease, Parkinson's disease, bipolar disorder, a mood disorder, an anxiety disorder, a cognitive disorder, or schizophrenia. 
 
     
     
       2. The method according to  claim 1 , wherein the sulphur containing heterocycle is substituted with 1, 2, or 3 chlorine or bromine atoms. 
     
     
       3. The method according to  claim 1 , wherein the compound is selected from the group consisting of:
 3,5-Diamino-6-[3-(2,5-dichlorothienyl)]-1,2,4-triazine [CEN-071]; 
 3,5-Diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine [CEN-079]; 
 5(3)-Amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2, 4-triazine [CEN-080]; 
 5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2, 4-triazine [CEN-194]; 
 5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-195]; 
 3,5-Diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine [CEN-122]; 
 3,5-Diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine [CEN-124]; 
 3,5-Diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine [CEN-125]; 
 3,5-Diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine [CEN-138]; and 
 and 
 3,5-Diamino-6-[2-(3-chlorobenzo[b]thiophenyl)]-1,2,4-triazine [CEN-114]. 
 
     
     
       4. The method according to  claim 1 , wherein the compound is 3, 5-Diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine [CEN-079]. 
     
     
       5. The method of  claim 1 , wherein the disorder is motor neurone disease. 
     
     
       6. The method according to  claim 3 , wherein the disorder is motor neurone disease. 
     
     
       7. A compound of general formula (I), or a salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       in which:
 X and Y are each N; 
 Z is a single bond or an optionally substituted linking group; 
 R1 is hydrogen, or a substituent group, or the Y nitrogen is unsubstituted; 
 R2 is amino or a substituent group; 
 N* is amino when R1 is hydrogen or ═NH when R1 is a substituent group; or 
 N* is a group NRaRb wherein Ra and Rb are independently H or an alkyl group; or 
 N* is an optionally substituted piperazinyl ring; and 
 A is a sulphur containing heterocycle substituted with halogen, alkyl or alkoxy. 
 
     
     
       8. The compound according to  claim 7 , wherein the sulphur containing heterocycle is optionally substituted with 1, 2, or 3 chlorine or bromine atoms. 
     
     
       9. The compound according to  claim 7 , wherein the compound is selected from the group consisting of:
 3,5-Diamino-6-[3-(2,5-dichlorothienyl)]-1,2,4-triazine [CEN-071]; 
 3,5-Diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine [CEN-079]; 
 5(3)-Amino-6-[3-(2,5-dichlorothienyl)]-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2, 4-triazine [CEN-080]; 
 5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-methyl-1,2,4-triazine [CEN-194]; 
 5(3)-Amino-6-{2-(3,4,5-trichloro)thienyl}-2,3(2,5)-dihydro-3(5)-imino-2-ethyl-1,2,4-triazine [CEN-195]; 
 3,5-Diamino-6-[2-(4,5-dibromothienyl)]-1,2,4-triazine [CEN-122]; 
 3,5-Diamino-6-[2-(5-bromothienyl)]-1,2,4-triazine [CEN-124]; 
 3,5-Diamino-6-[2-(3-bromothienyl)]-1,2,4-triazine [CEN-125]; 
 3,5-Diamino-6-[2-(5-chlorothienyl)]-1,2,4-triazine [CEN-138]; 
 and 
 3,5-Diamino-6-[2-(3-chlorobenzo[b]thiophenyl)]-1,2,4-triazine [CEN-114]. 
 
     
     
       10. The compound according to  claim 7 , wherein the compound is 3,5-Diamino-6-[2-(3,4,5-trichlorothienyl)]-1,2,4-triazine [CEN-079]. 
     
     
       11. A pharmaceutical composition comprising a compound of  claim 7  and a pharmaceutically acceptable carrier. 
     
     
       12. A pharmaceutical composition comprising a compound of  claim 8  and a pharmaceutically acceptable carrier. 
     
     
       13. A pharmaceutical composition comprising a compound of  claim 9  and a pharmaceutically acceptable carrier. 
     
     
       14. A pharmaceutical composition comprising a compound of  claim 10  and a pharmaceutically acceptable carrier.